Since the discovery of doxorubicin(adriamycin . . . Formula (1)) in 1969 by Di Marco and his coworker (Cancer Chemotherapy Reports, Part 1, 53, 33-41, 1969), the class of anthracyclin antitumor agents expanded greatly. In 1979 pirarubicin (THP-adriamycin . . . Formula (2)) was discovered by Umezawa et al during a search of new anthracyclin antibiotics. Among the 4′-O-substituted compounds, THP-adryamicin has less toxicity than other anthracyclin antitumor agents (Gan To Kagaku Ryoho, 15, 2819-27, 1988).
Anthracyclins antibiotics are known for its potent cytotoxic effect that is known to involve multiple mechanisms of cell killing. Generation of the oxygen radical by quinone group in its molecule promotes its DNA intercalating property and topoisomerase inhibitory mechanisms. All these effects lead to potent cancer cell killing. Pirarubicin, being relatively a new member of this group, has its unique DNA and RNA synthesis inhibitory action, more active than doxorubicin, with reduced cardiotoxicity.
Unfortunately the cytotoxic effect of these low molecular weight antitumor agents, such as anthracyclin or cis platinum, like many others, lack specificity to cancer cells that leads to sever side effects particularly towards rapidly dividing cells such as bone marrow cells and cells of the gastrointestinal tract. Furthermore, they affect slowly dividing or more stable tissues such as cardiac and hepatic tissues chronically. These side effects are the main factors limiting dose escalation of such powerful drugs.
To eliminate such side effects of these antitumor agents, the tissue distribution of drug plays a crucial role. We found that the molecular weight of the drugs are key to the question, namely drugs of low molecular weight drugs, for example, molecular size less than 10 KDa, are readily distributed in various normal organs tissues or tumor tissues indiscriminately through simple diffusion, and they are eventually eliminated into the bile by the liver and/or into urine through renal excretion. In case of doxorubicin and pirarubicin with molecular weight of 543.5 and 627.6, respectively, their distribution in the normal organs, i.e. the cardiac or bone marrow tissues, limit the effective use at high dose of these low molecular weight drugs for complete tumor eradication.
Problems to be Solved
This situation of toxicity and efficacy becomes great contrast between high molecular weight drugs vs. low molecular weight drugs. Namely macromolecular drugs of size above 40 KDa, where such drugs accumulate and remain more in tumor tissue for a long time due to the unique phenomenon of tumor tissue, which we discovered sometime ago: i.e. enhanced permeability and retention (EPR) effect of macromolecular or lipid drugs in solid tumors (Cancer Res., 44, 2115-2121, 1984; ibid, 46, 6387-92, 1986; Anticancer Res., 13, 1287-1292, 1993).
EPR phenomenon is attributed to anatomical and pathophysiological alternations in tumor tissues, such as increased vascular density by angiogenesis, lack of smooth muscle layer in solid tumor vessels and impaired lymphatic recovery. Pathophysiological changes in solid tumor are brought about by extensive production of vascular mediators such as bradykinin, nitric oxide, prostaglandins, matrix metalloprotinases(MMPs), VEGF/VPF and others resulting in enhancement of EPR effect that are not seen in normal tissues (e.g. Cancer Res., 58, 159-165, 1995; J. Control. Release, 74, 47-61, 2001; Advan. Enzyme Regul., 41, 189-207, 2001)
Previously, we had developed the first polymeric drug SMA [poly(styrene-co-maleic anhydride half n-butyrate)] conjugate with covalently linked to the proteinaceous antitumor agent, neocarzinostatin (NCS), which is named SMANCS (Japanese Patent (JP) No.1,549,302, JP 1,545,131, JP 2,556,865 and U.S. Pat. No. 2,556,865). This was the first antitumor polymeric drug in the world.
SMA confers unique pharmacological characters when compared with the parent low molecular weight drugs. Namely, SMA conjugates would become capable of rapid non-covalent bond to albumin, and hence that confers tumor tropism by EPR effect by virtue of increase of the molecular weight, thereby has excellent tumor targeting capacity.
Secondly, it has immunopotentiation (Oda T. et al., Proc. Soc. Exp Biol. Med., 181, 9-17, 1986; Masuda E and H Maeda, Cancer Res., 56, 1868-1873, 1996).